Alpha-isopropyl-alpha-(beta&#39;-dimethylamino propyl) phenyl acetonitrile, and a process of making same



2,934,557 I Patented Apr. 26, "1960 v intravenous administration has an average effective dose 2,934,557 of 7 mg./ kg., theco'mpound has a considerably higher or ISOPROPYL-u-(H-DIMETHYLAMINO PROPYL) PHENYL ACETONITRILE, A PROCESS present invention is .4 mg./ kg. when administered intravenously. Compared with codeine phosphate which, on

antitussive activity. I v.

This result is quite surprising sincesimilar amino OF MAKING SAME 5 nitriles having two asymmetric carbon atoms in neighboring position to each other are completely inefiective as wti runfii stiillimer, Eld%stirlli1 near Iaunover, andsiegfrieig antitussive agenm e, annovera cum, ermany, assignors The sul of he v i h a i Afkgengesenichaf" Hannover Germany tests we; ch nfirm ed b 2:1i ni h l iezi s p armacologlcal a cm'pomflon o emany 10 The following examples serve to illustrate the present No Drawing. Application April 7, 1958 invention without, however, limiting the same thereto.

Serial lilo. 726,628 0 Q EXAMPLE 1 Claims pnomy apphcamm Germany AP 1957 Preparation of a-isopropyl-a-(fl-dimethylamino propyl) 5 Claims. (Cl.'260--465) 15 phenyl acetonitrile 140 cc. of benzene and 24 g. of tit-isopropyl phenyl The present invention relates to a-1so-propyl-a(B -d1- methylamino propyl) phenylacetonitrile and acid addiaqetomtrile a added 2 of sodium amide tion salts thereof, and to a process of producing the same. i Sun-e? and re P for'one hour i coo It is one object of the present invention to provide 0 i 25 of LdlmethylammoTLchloro fq dlssolved a isoproyl a (B, dimethy1amino propyl) phenyl acetm n cc. of benzene, are added and stlrrmg and refluxnitrile and addition salts thereof with pharmacologically mg i h mlxmre 1s contmiled for 4 hours After h acceptable acids, which are highly eifective as antitussive macho completed i z 15 added to the macho m agents p ture. The benzene layer is separated from the aqueous Another object of the present invention is to provide a layer i 1s i i i by m/ am f 4 hydrochlonc acld' simple and efiective process of producing said a-isoproi acid so i 15 Iend ed a i The separated pyl-m-(B-dimethylamino propyl) phenyl acetonitrile and w 1S taken m ether 7 pdi i the ethereal acid addition salts thereof. 'tlOIl over sodium sulfate and distilllng 01f the ether, the Other objects of the present invention and advang crud? P propyl) tageous features thereof will become apparent as the phenyl acetonitrile s purified by d istilllation in a vacuum. scription proceeds. The compound boils at 138-146 C./3 mm.

u-Isopropyl-a-(fi-dimethy1amino propyl) phenyl aceto- EXAMPLE 2 nitrile of the formula Preparation of a-zsopropyl-u-( 3-dzmethylamm0 propyl) 2 1 phenyl acetonitrile CHFCHMCflCHFOHaMCH' 120 cc. of benzene and 16.3 g. of ot-(B-dimethylamino N propyl) phenyl acetonitrile, boiling at l34-l39 C./6 is prepared by reacting a-isopropyl phenyl acetonitrile mm. and prepared by reacting 15 g. of benzyl cyanide with 2dimethylamino-l-chloro propane in the presence and 17.5 g. of 2-dimethylamino-1-chloro propane in the of sodium amide or by reacting a-(H-dimethylamino pro- 40 presence of 6.5 g. of sodium amide, are added to 4 g; of pyl) phenyl acetonitrile with an isopropyl halogenide in sodium amide. After stirring and refluxing the mixture the presence of sodium amide. The resulting a-isopropylfor one hour, 11 g. of isopropyl bromide dissolved in 10 a-(l3-dimethylamino propyl) phenyl acetonitrile is puricc. of benzene are added thereto and stirring and refluxfied and, if desired, converted into. its acid addition salt. ing is continued for 4 hours. The reaction mixture is This compound is characterized by the presence of worked up as described hereinabove in Example 1. The two asymmetric carbon atoms in their carbon chain resulting compound is identical with that obtained acwhich asymmetric carbon atoms are separated from each cording to Example 1. other by a carbon atom. This position of the two asyma-Isopropyl-a-(;8-dimethylamino propyl) phenyl acetometric carbon atoms is apparently responsible for the nitrile forms a citurate which melts at 63 -64 C., on resurprisingly highand pronounced antitussive acitivity of crystallization from a mixture of alcohol and other the new compound. (1:10). It is hygroscopic an dreadily soluble in water. The antitussive activity of a-isopropylwt-(,3-dimethyl- It also forms a tartrate having a melting point of 64 amino propyl) phenyl acetonitrile was determined on C. onrecrystallization from ether. It is hygroscopic and guinea pigs in urethane narcosis. Coughing was induced readily soluble in water. by electrical irritation of the trachea by means of a blunt The citrate and the tartrate as well as other acid addiplatinum electrode. The used device is known to the art tion salts are prepared, for instance, by adding ethereal as Megatest apparatus. Irritation was caused by recsolutions of citric acid, tartaric acid, or suitable other tangular current impulses of a frequency of 10 per secacids to the solution of an equivalent amount of the base 0nd, each impulse having a duration of five thousandth dissolved in ether. Thereby, the citrate, tartrate or other of a second and an intensity of 5 ma. to 15 ma. The fits 0 addition salts precipitate. V of coughing were registered mechanically by recording For preparing the salts with a volatile acid, such as the movement of the abdominal walls. The tests were hydrochloric acid, hydrobromic acid and the like, said made only qualitatively. Only those of the animals were acids are introduced in the gaseous state in equivalent considered as giving a positive reaction to the new agent amounts into the ethereal solution of the base whereby in which coughing was completely suppressed on electri- 65 the acid addition salts are formed and are precipitated. cal irritation of the trachea. The average efiective dose The citrate, tartrate, and the like salts can also be ob- (EDSO) was determined by plotting a dose-effect diagram tained, for instance, by mixing methanolic solutions of according to Litchfield and Wilcoxon. equivalent amounts of the base and the respective acid The average effective dose of a isopropyl-a-(E-diand evaporating the solvent by heating on the water bath methylamino propyl) phenyl acetonitrile according to the in a vacuum.

In place of the acid addition salts with citric acid and tartaric acid, there may be prepared the salts with'other pharmaceutically acceptable acids, inorganic as well as organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, succinic acid, malic acid, benzoica-cid, nicotinic acid, and others. 7

I The new antitussive agent is preferably administered in the form of a cough sirup, cough drops, suppositories, as injectable solution, or the like. The following examples serve to illustrate suitable and eifective antitussive preparations containing the new compound or its acid addition salts without, however, limiting the present invention thereto.

EXAMPLE 3 Cough sirup An eifective cough sirup is composed as follows:

10 g. of the citrate of m-isopropyl-ot-(fi'-dimethylamino propyl) phenyl acetonitrile,

800 g. of sugar,

0.6 g. of the methyl ester of p-hydroxy benzoic acid known to the trade as Nipagin M, and

0.2 g. of the propyl ester of p-hydroxy benzoic acid known to the trade as Nipasol M are dissolved in 475 cc. of cherry juice, and the solution is made up to 1000 cc. by the addition of distilled water.

cc. of said cough sirup contain about 50 mg. of the new antitussive agent.

EXAMPLE 4 Cough Pimps 50 g. of the citrate of a-isopropyl-a-(;3-dimethylamino propyl) phenyl acetonitrile,

0.6 g. of the methyl ester of p-hydroxy benzoic acid known to the trade as Nipagin M, and

0.2 g. of the propyl ester of p-hydroxy benzoic acid known to the trade as Nipasol M are dissolved in distilled water, and the solution is made up to 1000 cc. by the addition of distilled water.

1 cc. of said cough drops contains about 50 mg. of the new antitussive agent.

As a minimum dose there are given three times daily 12 drops of said cough drop preparation. The preferred dose is three times'daily 20 drops and the maximum dose is three times daily 40 drops.

EXAMPLE 5 Suppository 100 g. of the citrate of a-isopropyl-a-(,B'-dimethylamino propyl) phenyl acetonitrile are incorporated into 2000 g. of cocoa butter.

The intimate and uniform molten mixture is poured into suppository molds to yield 1000 suppositories. Each suppository contains 100 mg. of the new antitussive compound.

EXAMPLE 6 Injeclable solution 110 g. of the citrate of a-isopropyl-a-(p-dimethylamino propyl) phenyl acetonitrile, are dissolved in 1100 cc. of saline solution.

tonitrile of the formula i 0.11, on, em

CHsCH-CCH2 H"N H; 0N 011i wherein indicates the asymmetric carbon atoms in said base, and its non-toxic acid addition salts.

2. The ot-lSOplOpY1-0t-( p-dimethylamino propyl) phenyl acetonitrile compound selected from the group consisting of a-is0propyl-e-(,8-dimethylamino propyl) phenyl acetonitrile of the formula wherein indicates the asymmetric carbon atoms in said base, and its non-toxic acid addition salts formed with an acid selected from the group consisting of citric, tartaric, hydrochloric, hydrobromic, nitric, sulfuric, succinic, malic, benzoic, and nicotinic acids.

3. aisopropyl-a-(B'-dimethylamino tonitrile.

4. The citrate of a-isopropyl-a-(B-dimethylamino propyl)phenylacetonitrile.

5. The tartrate of a-isopropyl-a-(;9'-dimethyl amino propyl) phenyl acetonitrile.

propyl) phenyl ace- References Cited in the file of this patent Stiihmer et al. (Germany), May 24, 1956, Patentanmeldung K21648, 3 pages.

Stiihmer at al. (Germany), June 14, 1956, Patentanmeldung K2l810, 3 pages. 

1. THE A-ISOPROPYL-A-(B''DIMETHYLAMINO PROPYL) PHENYL ACETONITRILE COMPOUND SELECTED FROM THE GROUP CONSISTING OF A-ISOPROPYL-A-(B-DIMETHYLAMINO PROPYL) PHENYL ACETONITRILE OF THE FORMULA 